PROJECT SUMMARY Oxytocin (OT) is a neuropeptide secreted by the hypothalamic paraventricular nucleus (PVN) and commonly associated with social behaviors, stress responses and drug-addiction. Previous studies have shown that OT has anxiolytic properties associated with cues in a cocaine seeking behavior paradigm, but the underlying mechanism remains unknown. Clinical studies show that cocaine abuse has long-term effects in the brain reward circuitry of those who use it. These changes might be responsible for a high risk of relapse even after years of abstinence. Given the fact that persons, places, paraphernalia and stress can induce the drug relapse, cocaine abuse elicit strong memories with its use. Our published data previously showed a role for OT in modulating the anxiety behavior elicited by the drug-paired environment. However, further experimentation is required to elucidate what other neurochemical substrates interact with OT within the mesolimbic system. One possible neuromodulatory substrate for this interaction is the endocannabinoid system (ECS), in particular the cannabinoid receptor type 1 (CB1) and the transient receptor potential vanilloid type-1 (TRPV1) receptors. The present sets of experiments aim to investigate the interactions between OT, CB1 and TRPV1 receptors within the dopamine mesolimbic system in the anxiogenic response triggered by cue- elicited cocaine seeking behavior. Our proposal is two-fold: first, we propose to determine the role of intranasal OT treatment in the anxiety response triggered by cue-elicited cocaine seeking behavior; second to establish CB1 and TRPV1 receptors interactions with OT actions within the NAc and medial prefrontal cortex in the anxiety response triggered by cue-elicited cocaine seeking behavior. The outcome of our proposal may contribute to a more detailed understanding of the cross-talk between OT and ECS on the anxiety elicited by the drug-associated cues. The present proposal further broadens the understanding of OT physiological actions as a novel therapeutic alternative for cocaine addiction. If funded, the present proposal will also provide our underrepresented minority undergraduate students at our Department of Biology with an intense research experience during the academic year and summer months. As mentor, I will offer student mentees with a strong scientific mentoring program that will promote active learning experiences, critical thinking, best practices in the ethical conduct in science, how to prepare successful applications to summer internships and graduate school abroad, effective writing skills in science, oral presentations in scientific forums and career counseling to enhance their professional capabilities. Moreover, the proposed experiments will further promote a strong research platform for successful training of Hispanic undergraduate students from the University of Puerto Rico Rio Piedras in the field of the neurobiology of drug addiction.